A neuroanatomical mechanism linking perinatal chemical exposure to prostate smooth muscle hyperactivity and altered voiding function

The historical focus of male lower urinary tract dysfunction (LUTD) has been benign prostatic enlargement and other aging-related processes. Little attention has been directed towards the influence of early life events on urinary physiology in advancing age. Here, we identify the intrauterine environment as a modifier of adult voiding function and risk factor for male LUTD. To model environmental chemical exposures, we exposed pregnant mice to the environmental contaminant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD, 1 µg/kg), coinciding with initiation of lower urinary tract development in male fetuses. Fetal TCDD exposure incites abnormal urodynamics in adult male mice, including increased urinary voiding frequency. TCDD also enhances adult prostate sensitivity to electrically evoked muscle contraction, suggesting increased autonomic tone. IUL TCDD exposure stably increases noradrenergic axon density beginning in the fetal period and persisting into adulthood. These changes are accompanied by increased abundance of a neurotrophin, Artemin (Artn), in the fetal prostate. This is the first evidence that intrauterine chemical exposures can reprogram prostate neuroanatomical development and drive prostatic smooth muscle hyperactivity in adulthood, which may create a susceptible phenotype for aging-related male lower urinary tract dysfunction. Overall design: Embryonic day (E) 13.5 C57BL/6J mice were dosed in utero with TCDD (1 microgram/kg maternal dose) or corn oil vehicle (control, 5 mL/kg). Urogenital sinuses were collected at E16.75, mesenchyme removed by trypic digestion and dissection, and the underlying epithelium (UGE) isolated for sequencing. Each treatment group consisted of 4 biological replicates and each replicate contained 5 or 6 individual UGEs that were pooled for RNA isolation.